This is a resubmission of a Mentored Patient-Oriented Career Development (K23) Award application to enhance the applicant's expertise in the study of innovative therapies for treatment-resistant major depression. The research component of this application includes a randomized, double-blind, placebo controlled trial of adjunctive pramipexole, a dopamine receptor agonist, for treatment-resistant depression. Subjects who improve with randomized treatment will also enter a continuation-phase pilot study. The application utilizes an innovative therapy and a simple, rigorous design to address an understudied disorder with major impact on public health. Preliminary studies suggest augmentation with dopamine receptor agonists such as pramipexole may be efficacious in these patients, though the optimum dose has not been established. The primary aim of this study will be to determine the efficacy of flexibly-dosed pramipexole compared to placebo. Secondary analyses will include clinical predictors of response. During the final two years of the award period, the candidate will develop a larger study building on this data and drawing on his formal training. The proposed study will be conducted at Massachusetts General Hospital in the Depression Clinical and Research Program, under the mentorship of Andrew Nierenberg, M.D. and co-mentorship of Maurizio Fava, M.D., A. John Rush, M.D., and Michael Thase, M.D., with consultation from a panel of local and national experts. The application also includes a rich didactic component combining formal coursework at the Harvard School of Public Health with tutorials in study design, assessment and management of treatment resistance, biostatistics, and bioethics. As the co-mentors are co-principal investigator or principal investigator in two large NIMH-funded effectiveness studies in mood disorders, the candidate will also participate in statistical review and ongoing analysis of both studies, applying skills developed in his coursework and tutorials. The proposed investigation and training program will provide critical skills, experience and data to aid the candidate in writing an R01 and becoming an independent investigator.